The University of Pittsburgh SCORR in COPD builds upon our long tradition of research in Chronic Obstructive Pulmonary Disease to propose a four project proposal which extends our previous work and our strong collaboration with the University of British Columbia. In project 1 PERIPHERAL MARKERS OF PHENOTYPIC HETEROGENEITY IN COPD; Our global hypothesis: COPD is a heterogeneous group of definable anatomic and physiologic disease processes, each with its own molecular and cellular processes that determine disease manifestation and progression; this will be tested in a well characterized cohort of 800 patients. In project 2 ADAPTIVE IMMUNE-INDUCED AIRWA INJURY IN COPD, we postulate that adaptive immune processes, driven by cognate recognition and responses to peptide antigens, cause or contribute to the airway injuries that result in COPD progression; this will be tested largely in human lung explants. In project 3 EGR-1: REGULATOR OF APOPTOSIS AND INFLAMMATION IN COPD we will translate results from human tissue experiments into mouse models to determine whether early growth response (EGR-1), regulates the coordinated expression of apoptosis and inflammation pathways in the context of cigarette smoke-induced chronic obstructive pulmonary disease (COPD). In project 4 CLINICAL INVESTIGATION OF AEROSOL IMMUNOTHERAPY IN COPD we hypothesize that modulation of identified immune responses in COPD subjects with specific biologic agents will ablate or ameliorate pathogenic mechanisms and alter the natural history of COPD.